The preclinical unit has focused on elucidating the molecular mechanism(s) of various antidepressant modalities. Highlights of the last year include: 1) In vitro and ex vivo studies in rat brain have clearly demonstrated that G i is a target of lithium's action. Thus, chronic lithium treatment significantly increases basal and cholera toxin stimulated cAMP accumulation while abolishing the pertussis toxin effect. Immunolabeling and ribosylation studies suggest that lithium stabilized G i in its inactive conformation, possibly via "cross talk" with PKC. 2) Chronic in vitro incubation of C6 glioma cells to a variety of antidepressants downregulates beta adrenergic receptors (beta ARs); these effects are accompanied by an increase in the beta AR K L/K H ratio, suggesting that antidepressants interfere with the action of G s. In marked contrast, the tricyclic anticonvulsant carbamazepine selectively upregulates beta2mRNA. 3) Chronic electroconvulsive shock (ECS) produces a region and isozyme subtype specific downregulation of PKC gamma in rat hippocampus. These results suggest potential therapeutic strategies for the prevention of ECT- induced memory impairment. ECS also increases the cholera toxin ribosylation in the striatum, which may explain the enhancement of dopaminergic function.